Gamma-aminobutyric acid type A receptors (GABAARs) are the main effectors of neuronal inhibition in the central nervous system. A large body of evidence has demonstrated that GABAARs and beta-adrenergic receptors (betaARs) exhibit physiological cross-talk and mutual regulation in vivo. Given that both receptors are proximately located in the neuronal plasma membrane, and recent findings that neurotransmitter receptors can heterodimerize, we decided to explore the possibility that there might be a direct interaction between GABAARs and betaARs. Here, we present preliminary evidence that GABAARs and beta1ARs heterodimerize following heterologous expression in HEK 293 cells as well as in native brain tissue by using immunoprecipitation. Using GST fusion protein affinity purifications, mutagenesis, and further immunoprecipitation studies, we propose to identify the specific amino acids in both the GABAAR and the beta1AR that mediate interaction. We will also use a multimodal approach to elucidate the functional consequences of GABAAR/beta1AR heterodimerization for both receptors. We will monitor the effect of coexpression and costimulation of the beta1AR on the physiology, regulation, and phosphorylation of the GABAAR. Additionally, we will investigate the effect of coexpression and costimulation of the GABAAR on the pharmacology and regulation of the beta1AR. Understanding the functional changes that accompany heterodimerization will likely provide insight into heretofore unexplained observations of GABAergic and beta-adrenergic physiological cross-talk in vivo. These studies represent an important step in understanding how the protein-protein interactions of a neurotransmitter receptor affect its intrinsic pharmacology and behavior. [unreadable] [unreadable]